HIV-1 -associated dementia (HAD) continues to be a clinically important issue in the era of highly active antiretroviral therapy (HAART). Because the etiology of HAD remains unclear, further research into its pathogenesis is warranted. We recently reported that HIV-1 DMAlevels (HIV DNA) are elevated in peripheral blood mononuclear cells (PBMC) in subjects diagnosed with HAD. Our preliminary investigation also suggests that the high PBMC HIV DNA is specifically within CD14*VCD16+ monocytes/macrophages (M/MO) rather than CD14+/CD16" M/Mct> or lymphocytes (CD14"). The central hypothesis to be addressed in this proposal is that peripheral HIV DNA in M/MO outside the central nervous system plays a pivotal role in the development of HAD. Utilizing 167 viably banked PBMC specimens from neurologically well-characterized individuals followed longitudinally within the HawaiiAging with HIV Cohort study, our grant submission proposes to: 1) further define the direct relationship between PBMC HIV DNA and HIV-1-associated neurocognitive impairment (NCI) particularly among those diagnosed to have Minor Cognitive Motor Disorder (MCMD); 2) clearly demonstrate that the high HIV DNA in PBMC in individuals with HAD is predominantly within CD14*/CD16+ M/MO and not lymphocytes; and 3) assess the mechanistic link between HIV DNA in M/MO and CD14VCD16" phenotype in an in vitro model. This in vitro model will determine the relative infectiviity of CD14VCD16* M/MO compared to CD14VCD16"M/MO, assess for a possible difference in HIV- 1 binding capacity of these 2 M/MO subsets, and also determine whether HIV-1-infection of the CD14+/CD16+ M/MO alters its cytokine secretory pattern. This project is innovative in its use of a pre- existing neurologically well-characterized cohort and the translational approach proposed to address this critically important issue. The significance lies in the knowledge to be gained on how HIV DNA in M/MO leads to HAD; why HAD and MCMD continue to be seen in the era of HAART; and in the potential that new therapeutic targets for prevention or treatment of HAD might be identified through this research. The proposal brings together a unique investigative team with multi-disciplinary expertise and established successful working relationships. This resource-rich team is well-positioned to conduct this investigation into the pathogenesis of HAD.